The overall goal of this project is to further understand why some individuals develop Staphylococcus aureus infection, and of those with bacteremia, only some develop adverse outcomes. Having used my K23 to create the world's largest collection of DNA from well-characterized patients with S. aureus bacteremia (n=400), I now propose to use this existing resource to evaluate genetic determinants of host susceptibility to S. aureus. We have observed that genetically distinct strains of mice exhibit a variable systemic response to S. aureus, and have identified a list of genes associated with susceptibility to S. aureus sepsis in the mouse model. The long-term objectives of this project are to: 1) determine whether polymorphisms within the genes identified in the mouse model are associated with susceptibility to S. aureus in a large cohort of humans with bacteremia, and 2) ultimately use these genes to identify novel interventions for the control of S. aureus infections. The specific hypothesis to be tested in this application is that identifiable host genetic factors are important determinants of risk for and severity of S. aureus infection. In order to test this hypothesis, we propose to: 1) Identify candidate genes associated with susceptibility to S. aureus in a murine sepsis model, using both in silico mapping and intercrosses between "sensitive" and "resistant" strains of inbred mice;2) Prioritize candidate genes and identify polymorphic variants associated with susceptibility to S. aureus infection;and 3) Test the importance of these polymorphic variants in patients with S. aureus bacteremia. The products of this grant will include an increased understanding of the role of genetic susceptibility to S. aureus in determining the severity of infection. The full value of the current application also includes the potential future benefit to the research community as a whole if associations between host genotype and clinical outcome, only possible to identify using such a large and well-characterized collection of DNA from infected patients, can be defined. This work is critical to furthering the understanding of a crucial medical problem because: 1) S. aureus is an emerging pathogen, and 2) interventions to reduce S. aureus morbidity require a better knowledge of the determinants of severity of infection. Understanding the host genetic determinants of disease severity in S. aureus infections will advance our understanding of staphylococcal pathogenesis and will enable key advances in protecting the public health from this pathogen.